Preclinical Evaluation of a Biofabricated Implant for Rotator Cuff Tendon-Enthesis Regeneration Project Summary/Abstract Rotator cuff injuries are a major clinical problem, leading to 250,000 surgical rotator cuff repair (RCR) procedures performed annually in the U.S. alone. Re-rupture rates following RCR are reported upwards of 95% with the current standard of care. Addressing the clinical need for improving rotator cuff healing, the goals of this research are to optimize the biomanufacturing, preservation and in vivo performance of a Biologically-enhanced Tissue ENgineered Device (Bio-TEND) for tendon and tendon-to-bone (enthesis) regeneration. Supported by multiple patents, Bio-TEND is: 1.) a well- characterized, anisotropic, resorbable collagen microfibrous graft electrospun from a benign solvent; 2.) engineered for high void to promote rapid cellular ingrowth and remodeling; and 3.) biomanufactured with clinical grade stem cells primed for tendon and fibrocartilage formation to promote enthesis regeneration. Our hypothesis is that Bio-TEND grafts will accelerate the production of new, host-generated, dense, regularly oriented tendon-like tissue and enthesis integration in a RCR model. We will accomplish two specific aims necessary for progressing through FDA approval and to commercialization. Aim 1: Establish Optimal Bio-TEND Biomanufacturing and Preservation Strategies. Aim 2: Assess Bio-TEND in a Chronic Rat RCR Model. Successful completion of our SBIR Phase I work will yield biomanufacturing of a therapeutic for RCR, including scale up, preservation and performance studies. This work will lead to pivotal testing in large animals and Mechanism of Action studies in SBIR Phase II, and human clinical trials in Phase III. Results of these SBIR studies will provide the data required for FDA submission and to successfully market the product. This project brings together investigators with the necessary complementary expertise in the translation of medical devices and cellular therapies (Dr. Francis, Embody), and tendon biology, biomechanics and animal models for RCR (Dr. Soslowsky, Penn), working together with world-class surgeons to develop this critical therapeutic.